Crystalline form of (r)-3-[(benzodioxolan-4-yl)oxy]-n,n-dimethyl-3-(4-fluorophenyl)propan-1-amine oxalate salt, process for its preparation and use

Abstract

The present application relates to compound (R)-3-[(benzo[d][1,3]dioxol-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propan-1-amine oxalate, crystal form and preparation method and application thereof and pharmaceutical composition containing therapeutically effective amount of the salt, crystal form of the compound, and use thereof in preparation of drugs for preventing and / or treating mental diseases.

Description

[0001] This application claims Chinese Patent Application No. 202311429289.4, filed on October 31, 2023, and application... The priority of Chinese patent application 202311429519.7, dated October 31, 2023, is incorporated herein by reference in its entirety. For reference only. Technical Field

[0002] This invention belongs to the field of pharmaceutical synthesis technology, and specifically relates to the crystal form of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate, its preparation method, and its application. Background Technology

[0003] Depression is one of the most common mental illnesses threatening human physical and mental health today. Currently, 3-5% of the world's population suffers from depression. Drug therapy is the primary treatment for depression. Major medications include: tricyclic antidepressants, such as imipramine; monoamine oxidase inhibitors, such as moclobemide; selective serotonin reuptake inhibitors, such as fluoxetine; selective norepinephrine reuptake inhibitors, such as ploroxetine; and dual serotonin and norepinephrine reuptake inhibitors, such as duloxetine.

[0004] Although many antidepressants are already in clinical use, due to low response rates, long onset times, and potential side effects of some drugs, a considerable number of patients still do not respond to various treatments, and some still require electroconvulsive therapy. Therefore, the development of antidepressants remains a hot topic in new drug research. Patent application WO2016101898A discloses a class of 3-[(benzo[d][1,3]dioxolane-4-yl)-oxy]-3-arylpropylamine compounds with antidepressant activity, all of which are hereby incorporated herein by reference. Summary of the Invention

[0005] Based on patent application WO2016101898A, the inventors further discovered that a specific R-isomer of 3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate (hereinafter referred to as Compound I) has good antidepressant activity, and compared with the S-isomer and racemic mixture, Compound I has a lower minimum effective dose, median effective dose and less toxicity.

[0006] Furthermore, the crystal structure of a pharmaceutically active ingredient often affects its chemical stability. Differences in crystal form, preparation method, and storage conditions can lead to variations in the compound's crystal structure, sometimes even resulting in other crystal forms. Generally, amorphous drug products lack regular crystal structures and often exhibit other defects, such as poor product stability, difficulty in filtration, tendency to agglomerate, and poor flowability. These differences often lead to difficulties in scale-up production. Therefore, improving various properties of compounds through crystal morphology is essential, requiring in-depth research to find new crystal forms with high purity and good chemical stability.

[0007] The technical problem to be solved by the present invention is to provide a compound as shown in Formula I below, namely (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate, and its crystal forms I, II and III.

[0008]

[0009] The present invention also provides methods for preparing crystal form I, crystal form II and crystal form III, and the use of crystal form I, crystal form II or crystal form III in the preparation of medicaments for the prevention and / or treatment of mental illnesses.

[0010] The above-mentioned crystal forms have good crystal form stability and chemical stability, are easier to obtain, facilitate industrial preparation, and can be better applied in clinical practice. Detailed Implementation

[0011] The object of the present invention is to provide a compound as shown in Formula I below, namely (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate

[0012]

[0013] The present invention also provides a crystal form I of the compound (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate as shown in Formula I, wherein: the X-ray powder diffraction pattern of crystal form I includes diffraction peaks located at 2θ of 9.33±0.2°, 15.64±0.2° and 23.63±0.2°.

[0014] Preferably, the X-ray powder diffraction pattern of crystal form I further includes diffraction peaks located at 2θ of 16.48±0.2°, 19.77±0.2°, 20.06±0.2°, 22.09±0.2°, 23.06±0.2° and 24.21±0.2°.

[0015] More preferably, the crystal form I is subjected to Cu-Kα radiation, and its X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, are shown in Table 1.

[0016] Table 1. XRPD diffraction data of crystal form I

[0017]

[0018]

[0019] In one embodiment, the Raman spectrum of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form I is at 3069.2 ± 2 cm⁻¹. -1 2966.6±2cm -1 1753.3±2cm -1 1603.0±2cm -1 1447.2±2cm -1 1354.6±2cm -1 1218.8±2cm -1 1158.8±2cm -1 1051.4±2cm -1 927.5±2cm -1 867.0±2cm -1 833.6±2cm -1 721.2±2cm -1 and 674.3±2cm -1 One or more characteristic peaks are shown in the image.

[0020] In one embodiment, the melting endothermic peak of the DSC plot of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form I is selected from 126.8°C to 132.2°C, preferably 129.8°C.

[0021] More preferably, the X-ray powder diffraction pattern of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form I is essentially as follows: Figure 1 As shown; its Raman spectrum is basically as follows. Figure 2 As shown; its DSC spectrum is basically as follows. Figure 3 As shown, its TG spectrum is basically as follows: Figure 4 As shown.

[0022] The present invention also provides a crystal form II of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate, wherein the X-ray powder diffraction pattern of crystal form II includes diffraction peaks located at 2θ of 15.07±0.2°, 16.71±0.2°, and 22.76±0.2°.

[0023] Preferably, the X-ray powder diffraction pattern of crystal form II also includes diffraction peaks located at 2θ of 11.38±0.2°, 16.01±0.2°, 19.71±0.2°, 22.05±0.2° and 29.03±0.2°.

[0024] More preferably, the crystal form II is subjected to Cu-Kα radiation, and its X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, are shown in Table 2.

[0025] Table 2 XRPD diffraction data for crystal type II

[0026]

[0027]

[0028] In one embodiment, the Raman spectrum of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form II is at 3073.5 ± 2 cm⁻¹. -1 2972.0.±2cm -1 1603.0±2cm -1 1460.4±2cm -1 1357.4±2cm -1 1219.1±2cm -1 1154.5±2cm -1 886.5±2cm -1 862.9±2cm -1 826.3±2cm -1 772.3±2cm -1 and 699.1±2cm -1 One or more characteristic peaks are shown in the image.

[0029] In one embodiment, the melting endothermic peak of the DSC plot of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form II is selected from 116.9°C to 123.0°C, preferably 120.2°C.

[0030] More preferably, the X-ray powder diffraction pattern of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form II is essentially as follows: Figure 5 As shown; its Raman spectrum is basically as follows. Figure 6 As shown; its DSC spectrum is basically as follows. Figure 7 As shown, its TG spectrum is basically as follows: Figure 8 As shown.

[0031] The present invention also provides a crystal form III of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate, wherein the X-ray powder diffraction pattern of crystal form III includes diffraction peaks located at 2θ of 13.64±0.2°, 15.14±0.2° and 22.86±0.2°.

[0032] Preferably, the X-ray powder diffraction pattern of crystal form III further includes diffraction peaks located at 2θ of 8.27±0.2°, 11.24±0.2°, 16.18±0.2°, 17.06±0.2°, 18.01±0.2°, 18.36±0.2°, 18.99±0.2° and 23.18±0.2°.

[0033] More preferably, the crystal form III uses Cu-Kα radiation, and its X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, are shown in Table 3.

[0034] Table 3 XRPD diffraction data for crystal type III

[0035]

[0036]

[0037] In one embodiment, the Raman spectrum of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form III is at 3075.9 ± 2 cm⁻¹. -1 2970.6±2cm -1 1603.3±2cm -1 1500.2±2cm -1 1458.1±2cm -1 1219.3±2cm -1 1154.8±2cm -1 1045.3±2cm -1 885.7±2cm -1 862.8±2cm-1 826.5±2cm -1 772.4±2cm -1 and 699.6±2cm -1 One or more characteristic peaks are shown in the image.

[0038] In one embodiment, the melting endothermic peak of the DSC of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form III is selected from 119.7°C to 125.1°C, preferably 122.6°C.

[0039] More preferably, the X-ray powder diffraction pattern of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form III is essentially as follows: Figure 9 As shown; its Raman spectrum is basically as follows. Figure 10 As shown; its DSC spectrum is basically as follows. Figure 11 As shown, its TG spectrum is basically as follows: Figure 12 As shown.

[0040] According to any embodiment of the first aspect of the present invention, crystal form I, crystal form II and crystal form III can be prepared by conventional crystallization methods such as solvent removal method, antisolvent method and static crystallization method. Selecting appropriate solvents, crystallization conditions, etc., can be achieved by those skilled in the art through experiments and screening based on their technical knowledge.

[0041] For example, the solvent removal method involves completely dissolving the sample using a suitable solvent system and then removing the solvent slowly, at a constant rate, or rapidly under certain conditions (such as vacuum or a specific temperature), thereby promoting the precipitation and formation of crystals.

[0042] The antisolvent method involves adding a solute from a good solvent to a poor solvent, thereby significantly reducing the solubility of the solute in the mixed solvent system, causing it to coagulate or precipitate and form solid crystals.

[0043] The static crystallization method involves dissolving the solute in a solvent and then allowing it to stand, allowing the solute molecules in the solution to gradually aggregate, nucleate, and grow into crystals under the influence of factors such as concentration gradient, temperature gradient, or solvent evaporation.

[0044] The term "good solvent" as used in this invention refers to a solvent that can effectively dissolve a specific solute, allowing the solute molecules to be fully dispersed and extended in the solvent, including readily soluble, soluble, slightly soluble, or minimally soluble. The term "bad solvent" refers to a solvent that cannot effectively dissolve a specific solute, resulting in low solubility of the solute, such as almost insoluble or insoluble. Based on the solubility experiment described in detail in Test Example 1 below, a good solvent, a bad solvent, or a combination thereof suitable for crystal form preparation can be conveniently selected. This invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate as described above, or crystal form I, crystal form II, or crystal form III as described above, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0045] The present invention further relates to the use of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate as described above, or crystal form I as described above, or crystal form II as described above, or crystal form III as described above, or pharmaceutical compositions thereof, in the preparation of a medicament.

[0046] In a preferred embodiment of the present invention, the drug is used as a medicine for the prevention and / or treatment of mental illnesses.

[0047] In a further preferred embodiment of the present invention, the mental illness is selected from one or more of anxiety disorder, obsessive-compulsive disorder, depression, phobia and schizophrenia.

[0048] In a further preferred embodiment of the present invention, the mental illness is depression.

[0049] General terms and definitions

[0050] The different expressions such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", and "X is A, B and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0051] "Room temperature" refers to a temperature between 10°C and 40°C. In some embodiments, "room temperature" refers to a temperature between 15°C and 30°C; in other embodiments, "room temperature" refers to a temperature between 18°C ​​and 25°C.

[0052] "Optional" or "optionally" means that the event or environment described below may, but does not necessarily, occur, and this description includes the possibility that the event or environment may or may not occur. The term "NMP" is N-methylpyrrolidone; the term "DMF" is N,N-dimethylformamide; the term "DMSO" is dimethyl sulfoxide; and the term "EA" is ethyl acetate.

[0053] In this invention, "crystal form I" refers to crystal form I of compound of formula I.

[0054] The “crystal form II” mentioned in this invention refers to crystal form II of the compound of formula I.

[0055] The “crystal form III” mentioned in this invention refers to crystal form III of the compound of formula I.

[0056] The "boiling point" mentioned in this invention refers to the boiling point or azeotropic point of a pure solvent or a mixed solvent.

[0057] "Pharmaceutical composition" refers to a mixture containing one or more compounds described in this invention, or physiologically / pharmaceutical acceptable salts or prodrugs thereof, along with other chemical components, such as physiologically / pharmaceutical acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0058] "Pharmaceutically acceptable salt" refers to the salt of the compounds of this invention, which is safe and effective when used in mammals and has the intended biological activity.

[0059] The term "crystalline solid" as used in this specification refers to a crystalline substance with a specific crystal form, consisting of a regular arrangement of atoms, ions, and molecules that constitute a solid. Unless otherwise specified, "crystal" is synonymous with "crystalline solid" and "crystal form" in this specification. The degree of crystallinity of a crystalline morphology can be determined using various techniques, including X-ray powder diffraction, water adsorption-desorption, differential scanning calorimetry, solution colorimetry, and solubility characteristics.

[0060] Crystalline solids can be single crystals, twins, polycrystalline, etc., but are usually single crystals or mixtures thereof. There are no particular limitations on the morphology (shape) of the crystals; for example, they can be triclinic, monoclinic, orthorhombic (rectangular), tetragonal, cubic, trigonal (rhombohedral), hexagonal, etc., or they can be spherulites, skeletal crystals, bark-like crystals, needle-like crystals (e.g., whisker-like crystals), etc. There are no particular limitations on the size of the crystals; for example, based on laser diffraction, the average grain size of the crystals can be 0.5 μm to 1 mm, preferably around 1 to 500 μm.

[0061] Furthermore, the crystalline solid of the compound can also adsorb moisture due to changes in relative humidity. That is, changes in external humidity can allow water molecules in the air to easily enter and exit the crystalline solid in the form of water of crystallization. Regarding such crystalline solids, even if the X-ray powder diffraction pattern changes with the moisture content, as long as the characteristic peaks described in this specification are present, it can be interpreted as the same crystalline solid. This moisture can be any of the residual solvents such as water of crystallization or adhering water.

[0062] "Polymorphism" or "polymorphic compounds" refers to crystal forms that have the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions that constitute the crystal. Although polymorphs have the same chemical composition, they differ in their packing and geometric arrangement, and may exhibit different physical properties, such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, and similar properties. The relative stability between the two solid phases is interchanged based on their temperature-stability relationship. This phenomenon of compounds existing in different lattice structures is called pharmaceutical polymorphism.

[0063] Crystal structures disclosed or claimed in this invention may exhibit similar but not identical analytical properties within a reasonable margin of error, depending on experimental conditions, purity, equipment, and other commonly used variables known to those skilled in the art. Accordingly, it will be apparent to those skilled in the art that various modifications and variations can be made within the scope and spirit of this invention without departing from its scope. Other embodiments of the invention will be apparent to those skilled in the art based on consideration of the specification and practice of the invention disclosed herein. The applicant expects this specification and examples to be considered exemplary and not limiting of its scope.

[0064] "X-ray powder diffraction pattern" or "XRPD" refers to the pattern obtained according to Bragg's formula 2d sinθ=nλ (where λ is the wavelength of the X-ray). The diffraction order n can be any positive integer, generally taking the first-order diffraction peak (n=1). The "2θ or 2θ angle" mentioned refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree. When X-rays are incident at a grazing angle θ (the complementary angle of the incident angle, also known as the Bragg angle) onto an atomic plane of a crystal or a partial crystal sample with a lattice spacing of d, the Bragg equation is satisfied, thus allowing the measurement of this set of X-ray powder diffraction patterns.

[0065] As is known to those skilled in the art, XRPD may exhibit certain displacement and intensity deviations due to sample ply thickness, detection methods, conditions, and instruments. Samples of the same crystal form typically possess the same major XRPD characteristic peaks, but operational errors may exist. When samples of the same crystal form obtained by those skilled in the art using appropriate methods are detected using the same instruments and methods, the characteristic peak error is usually within ±0.2°. However, different technicians using different instruments may occasionally encounter a few characteristic peaks with errors exceeding this range. Errors within ±0.5° or ±0.3° should be considered as XRPD characteristic peaks of the same crystal form. Therefore, as a specific example of the crystal form of this invention, its XRPD is shown in spectrum X. However, those skilled in the art understand that when the 2θ displacement deviation of the key characteristic peak is within ±0.5°, ±0.3°, or ±0.2°, especially around ±0.2°, it can be considered as the same crystal form and can be interpreted as within the scope of protection of this invention.

[0066] Furthermore, the absolute and relative intensities of the peaks shown in the aforementioned tables and figures may vary due to various factors, such as the effect of the selective orientation of the crystalline solid on the X-ray beam, the influence of coarse particles, the purity of the analyzed substance, or the degree of crystallinity of the sample. Additionally, the peak positions may shift depending on variations in sample height. Moreover, if different wavelengths are used for measurement, different shift values ​​are obtained according to the Bragg formula (nλ = 2dsinθ), and these different XRPD patterns obtained by using different wavelengths are also within the scope of this invention.

[0067] "Interplanar spacing or interplanar spacing (d-value)" refers to the division of a space lattice into juxtaposed parallelepiped units by three non-parallel unit vectors a, b, and c, which connect adjacent points. The space lattice is then divided according to these defined parallelepiped unit vectors, resulting in a linear grid called a space lattice or crystal lattice. Lattice and crystal lattice represent the periodicity of crystal structure using geometric points and lines, respectively. Different crystal planes have different interplanar spacings (i.e., the distance between two adjacent parallel crystal planes); the unit is 1 / d. Or E.

[0068] "Relative intensity (I%)" refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak when the intensity of the first strongest peak in an X-ray powder diffraction pattern (XRPD) is 100%.

[0069] Differential scanning calorimetry (DSC) determines the transition temperatures of a crystal when it absorbs or releases heat due to changes in its crystal structure or melting. For the same crystal form of the same compound, the error in thermal transition temperature and melting point can be within about 5°C, typically within about 3°C, in consecutive analyses. When describing a compound as having a given DSC peak or melting point, this refers to ±5°C of that DSC peak or melting point, essentially taking this temperature variation into account. DSC provides an auxiliary method for distinguishing different crystal forms. Different crystal forms can be identified based on their different transition temperature characteristics. It should be noted that for mixtures, their DSC peaks or melting points may vary over a wider range. Furthermore, since decomposition occurs during the melting process, the melting temperature is related to the heating rate.

[0070] Thermogravimetric analysis (TG) is a common method for determining the thermal stability of compounds. In this invention, TG can also be used to determine the hydration state of compounds. The heating rate during the test will have a certain impact on the chromatogram. The error of TG can be within approximately ±0.5% by mass.

[0071] Fourier transform Raman spectroscopy (FT-Raman) is generally used to study molecular structure and chemical bonds, and can also be used as a method for characterizing and identifying chemical species. In this invention, FT-Raman spectroscopy is used to characterize molecular structure and crystal form. The peak position error range of FT-Raman spectroscopy can be ±2 cm⁻¹. -1 .

[0072] "Amorphous," "amorphous form," or "amorphous structure" refers to matter formed when the particles (molecules, atoms, ions) are arranged non-periodically in three-dimensional space. Its characteristic feature is a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous / amorphous is a special physical form of solid matter, and its locally ordered structural features suggest a close connection with crystalline substances.

[0073] "Basically as shown in the figure" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks are shown in the X-ray powder diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum.

[0074] In the context of this invention, when the terms "about" or "approximately" are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, for those skilled in the art, the term "about" or "approximately" means within an acceptable standard error range of the average. Whenever a number with a value of N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where "+ / -" means addition or subtraction.

[0075] In this invention, mental illnesses refer to diseases characterized by varying degrees of impairment in cognitive, emotional, volitional, and behavioral activities due to brain dysfunction caused by various biological, psychological, and social environmental factors. Mental activities include cognitive activities (composed of sensation, perception, attention, memory, and thinking), emotional activities, and volitional activities. These processes are interconnected and closely coordinated, maintaining the unity and integrity of mental activities. Mental illnesses are mainly divided into mild and severe mental illnesses. Common mild mental illnesses include obsessive-compulsive disorder (OCD) and depression. Common severe mental illnesses include schizophrenia. Mild mental illnesses mainly manifest as emotional disturbances (such as anxiety and depression) and thought disturbances (such as obsessive thoughts), but the patient's cognitive, logical reasoning abilities, and insight remain largely intact. In contrast, early-stage patients with severe mental illnesses such as schizophrenia may also exhibit anxiety and obsessive thoughts, but their cognitive and logical reasoning abilities become very poor, and they almost completely lose insight. Organic or toxic mental illnesses caused by brain lesions need to be distinguished from general functional mental illnesses. Mild mental illnesses include anxiety disorders, obsessive-compulsive disorder, depression, and phobias. Severe mental illnesses include schizophrenia. Various mental illnesses occur when the body is affected by harmful internal or external factors, causing dysfunction in brain function. Mental illness manifests when the entire mental activity is significantly abnormal or disordered, and the integrity and unity of mental activity are disrupted. If the primary issue is a weakening of mental activity capacity without severe and persistent mental disorder, it manifests as neurosis; if the development of mental activity is hindered, it manifests as intellectual disability.

[0076] Depression is mainly characterized by low mood, loss of interest, pessimism, slow thinking, lack of initiative, self-blame and guilt, poor appetite and sleep, worry about having various diseases, feeling discomfort in many parts of the body, and in severe cases, suicidal thoughts and behaviors.

[0077] The term "treatment" refers to any indication of successfully treating or improving an injury, disease, lesion, or condition, including any objective or subjective parameters, such as the elimination, relief, or reduction of symptoms, or making the patient more tolerant of the injury, lesion, or condition; slowing the rate of degeneration or worsening; making the final outcome of degeneration less likely to cause debilitating effects; or improving the patient's physical or mental health. Treatment or improvement of symptoms can be based on objective or subjective parameters, including the results of physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0078] The term “treatment” and its related expressions include prevention of disease, lesion, ailment or illness (e.g., prevention of the development of one or more symptoms of the disease, ailment or illness described herein).

[0079] "Effective amount" is an amount sufficient to achieve a specified purpose (e.g., to achieve the effect of application, to treat a disease, to reduce enzyme activity, to increase enzyme activity, or to reduce one or more symptoms of a disease or ailment).

[0080] An example of an "effective dose" is an amount sufficient to treat, prevent, or reduce one or more symptoms of a disease; it may also be called a "therapeutic effective dose." A "preventive effective dose" of a drug is an amount that, when administered to a subject, will have the expected preventive effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, lesion, or disorder, or reducing the likelihood of the onset (or recurrence) of such an injury, disease, lesion, or disorder, or its symptoms. A single dose may not produce complete prevention, and may only occur after a series of doses. Therefore, a preventive effective dose can be administered in one or multiple doses. The exact dosage will depend on the therapeutic purpose and can be determined by a person skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (Vols. 1–3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th ed., 2003, edited by Gennaro, Lippincott, Williams & Wilkins).

[0081] The “reduction” of one or more symptoms (and the grammatical equivalent of the phrase) means to reduce the severity or frequency of the symptoms, or to eliminate the symptoms.

[0082] "Control" or "controlled experiment" is used in its general sense and refers to an experiment in which subjects or reagents are treated as in a parallel experiment, but the experimental procedures, reagents, or variables are omitted. In some cases, a control is used as a comparative standard to evaluate the effectiveness of an experiment.

[0083] As used herein, the term "administration" means oral administration, suppository administration, surface contact, intravenous administration, non-enteric administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, or subcutaneous administration to a subject, or administration via implantation of a slow-release device, such as a micro-osmotic pump. Administration can be carried out via any route, including non-enteric and mucosal administration (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or percutaneous). Non-enteric administration includes, for example, intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, percutaneous patches, etc.

[0084] Beneficial effects

[0085] The compound of Formula I of this invention exhibits good antidepressant activity, and compared to its S-isomer and racemic counterpart, it has a lower minimum effective dose, median effective dose, and less toxicity. Furthermore, its salt crystal form has high purity and good crystal stability; specifically, the crystal form shows minimal purity variation, high chemical stability, good solubility, and good bioavailability as determined by HPLC. In particular, crystal form I of the compound shown in Formula I has high purity, good crystal stability, almost no hygroscopicity, and good bioavailability; it meets the pharmaceutical requirements for production, transportation, and storage, is easy to prepare, facilitates industrial-scale production, and has a stable, repeatable, and controllable production process, making it suitable for industrial production. Attached Figure Description

[0086] Figure 1 XRPD illustration of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form I.

[0087] Figure 2 Raman spectroscopy for (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form I.

[0088] Figure 3 DSC illustration of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form I.

[0089] Figure 4TG illustration of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form I.

[0090] Figure 5 XRPD illustration of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form ⅠI.

[0091] Figure 6 Raman spectroscopy for (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form ⅠI.

[0092] Figure 7 DSC illustration of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form Ⅱ.

[0093] Figure 8 TG illustration of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form ⅠI.

[0094] Figure 9 XRPD illustration of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form I and II.

[0095] Figure 10 Raman spectroscopy for (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form I and II.

[0096] Figure 11 DSC illustration of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form IIⅠ.

[0097] Figure 12 TG illustration of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form IIⅠ.

[0098] Figure 13 The image shows the 30-day XPRD of crystal form I under different influencing factors.

[0099] Figure 14The XPRD diagram for crystal form II under different influencing factors over 30 days is shown.

[0100] Figure 15 The XPRD diagram for crystal form III under different influencing factors over 30 days is shown. Specific Implementation

[0102] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0103] Experimental instruments or reagents:

[0104] Reagent source

[0105] Table 4. Reagent Sources

[0106]

[0107]

[0108] Experimental instruments and testing conditions

[0109] 1. X-ray Powder Diffraction (XRPD)

[0110] Instrument model: Bruker D8 Focus powder X-ray diffractometer.

[0111] X-ray parameters: Cu / Kα

[0112] Voltage: 40 kV

[0113] Current: 40 milliamperes (mA)

[0114] Scan range: from 3.0 to 60 degrees

[0115] Scan step size: 0.02 degrees

[0116] Scanning speed: 0.5 seconds / step

[0117] 2. Differential Scanning Calorimeter (DSC) instrument model: Netzsch DSC 200F3 differential scanning calorimeter (Germany)

[0118] Purge gas: Nitrogen

[0119] Heating rate: 10.0 K / min

[0120] Temperature range: 35-160℃

[0121] 3. Thermogravimetric Analysis (TG)

[0122] Instrument Model: Netzsch TG209F3 Thermogravimetric Analyzer (Germany)

[0123] Purge gas: Nitrogen

[0124] Heating rate: 10.0 K / min

[0125] Temperature range: 35-250℃

[0126] 4. Fourier Raman Spectrometer (FT-RM)

[0127] Instrument Model: Thermo Scientific DXR Smart Raman Spectrometer; Aperture: 50μm

[0128] Exposure time: 10s

[0129] Number of exposures: 32

[0130] Laser: 780nm

[0131] Laser energy: 150mw

[0132] Synthesis Examples

[0133] Example 1: Preparation of (R)-N,N-dimethyl-3-(4-fluorophenyl)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]propylamine oxalate (Compound I)

[0134]

[0135] 1.1 Preparation of 3-(dimethylamino)-1-(4-fluorophenyl)-1-propanone hydrochloride (intermediate I)

[0136] 2 kg (14.48 mol) of p-fluoroacetophenone, 868.6 g (28.96 mol) of paraformaldehyde, 1.77 kg (21.71 mol) of N,N-dimethylamine hydrochloride and 6 L of anhydrous ethanol were added to a 20 L glass reaction flask. Stirring was started, and the temperature was raised to 60 °C. 120 mL of concentrated hydrochloric acid was added. After the addition was complete, the temperature was raised to 90 °C and the reaction was carried out for 17 hours.

[0137] After the reaction was complete, the mixture was concentrated under reduced pressure to remove 3L of ethanol. The mixture was then cooled gradually to allow crystals to crystallize. After cooling to 0–10°C, the mixture was stirred for 1.5 hours. The mixture was then filtered, the filter cake was washed with ethyl acetate, and the resulting solid was dried to constant weight to give 2.52 kg of white solid.

[0138] 1.2 Preparation of 3-(dimethylamino)-1-(4-fluorophenyl)-1-propanol (intermediate II)

[0139] 2.5 kg (10.81 mol) of 3-(dimethylamino)-1-(4-fluorophenyl)-1-propanone hydrochloride and 3.0 kg of methanol were added to a 20 L reaction flask. Stirring was started, and the temperature was controlled at -20 to 0 °C. Sodium hydroxide aqueous solution (432.4 g sodium hydroxide and 1.0 kg purified water) was added. Sodium borohydride 265.8 g (7.03 mol) was added in portions. After the addition was complete, the temperature was raised to 20 °C and the reaction was allowed to proceed for 2 hours.

[0140] After the reaction was complete, the mixture was filtered, and the filtrate was transferred to a 20L glass reaction flask. The methanol was removed by concentration under reduced pressure. Then, 2.0 kg of drinking water and 1 kg of ethyl acetate were added for extraction. After separation, the aqueous phase was extracted twice more with ethyl acetate (500 g / time). The organic phases were combined and washed twice with 20% sodium chloride solution. The organic phase was dried with 500 g of anhydrous magnesium sulfate, filtered, and the filter cake was rinsed with 500 g of ethyl acetate. The ethyl acetate was then removed by concentration under reduced pressure to obtain 2.0 kg of a light yellow oily substance.

[0141] 1.3 Preparation of (R)-3-(dimethylamino)-1-(4-fluorophenyl)-1-propanol R-mandelate (intermediate III)

[0142] Add 2.0 kg (10.27 mol) of 3-(dimethylamino)-1-(4-fluorophenyl)-1-propanol and 2.5 kg of toluene to a 20 L reaction flask, start stirring, then add 0.9 kg of anhydrous ethanol, heat to 55 °C, add 1.25 kg of R-(-)-mandelic acid, heat to 90 °C, and react for 1 hour.

[0143] After the reaction was complete, the temperature was lowered to allow crystals to crystallize, and the temperature was maintained at 10–20 °C while stirring for 1.5 hours. The mixture was then filtered, and the filter cake was washed with 0.6 kg of anhydrous ethanol. The resulting solid was dried to constant weight to obtain 1.6 kg of a white solid.

[0144] 1.4 Preparation of (R)-N,N-dimethyl-3-(4-fluorophenyl)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]propylamine p-hydroxybenzoate (intermediate IV)

[0145] 1.3 kg of (R)-3-(dimethylamino)-1-(4-fluorophenyl)-1-propanol R-mandelate was added to a 20 L reaction flask. Sodium hydroxide solution (148 g sodium hydroxide and 738 g drinking water) was added, and stirring was started. The mixture was stirred for 30 minutes, and 1 kg of ethyl acetate was added for extraction. The aqueous phase was extracted twice more with ethyl acetate (500 g each time). The organic phases were combined and washed twice with saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 695 g of colorless liquid for later use.

[0146] Add 690g(R)-3-(dimethylamino)-1-(4-fluorophenyl)-1-propanol and 2.3kg dimethyl sulfoxide to a 20L reaction flask, start stirring, add 589g potassium tert-butoxide in batches, control the temperature to about 45℃, then add 637g 3-fluoro-1,2-methylenedioxybenzene. After the addition is complete, raise the temperature to 70℃ and react for 5 hours.

[0147] After the reaction was complete, the mixture was cooled to room temperature, and 1.7 kg of drinking water and 1.4 kg of ethyl acetate were added for extraction. The aqueous phase was then extracted once more with 1.0 kg of ethyl acetate. The organic phases were combined and washed three times with saturated sodium chloride solution. The organic phase was dried with anhydrous magnesium sulfate, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain 1.15 kg of a brownish-black oily substance. A vacuum distillation apparatus was set up, and the oily substance was added to a 2 L (24#) single-necked flask. Vacuum distillation was carried out, with the external temperature controlled at 160–200 °C and the steam temperature at 140–170 °C. The fraction was collected and weighed to obtain 645 g of a light yellow oily liquid.

[0148] 637 g of the above light yellow oily liquid and 2.0 kg of ethyl acetate were added to a 20 L reaction flask, followed by 291 g of p-hydroxybenzoic acid. The mixture was stirred, heated, and reacted at 70 °C for 1 hour. The mixture was then cooled gradually to allow crystals to crystallize. The crystals were filtered, and the filter cake was washed twice with ethyl acetate. The resulting solid was dried to constant weight to obtain 570 g of white solid.

[0149] Add 570g of the crude product to a 5L reaction flask, add 1.7kg of anhydrous ethanol, reflux at 80℃ for 1 hour, cool naturally to room temperature, stir in an ice bath for 1 hour; filter, wash the filter cake with 285g of anhydrous ethanol, and dry the obtained solid to constant weight to obtain 450g of white solid.

[0150] 1.5 Preparation of (R)-N,N-dimethyl-3-(4-fluorophenyl)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]propylamine oxalate

[0151] Add 440g of the above white solid to a 5L reaction flask, add sodium hydroxide solution, stir for 30 minutes, extract three times with ethyl acetate (400mL each time), wash the organic phase three times with saturated sodium chloride solution, dry with anhydrous magnesium sulfate, filter, concentrate under reduced pressure, and obtain 298g of residue.

[0152] Oxalic acid salt formation: Add 596g of ethyl acetate to 298g of the above residue, heat to 70℃, add ethyl acetate solution of oxalic acid (84.55g) in portions, adjust pH to approximately 5, precipitate a solid, add 70g of ethanol and 300g of ethyl acetate, stir for 1 hour, cool to room temperature, then place in an ice bath to cool and crystallize, filter, wash the filter cake with ethyl acetate, dry the obtained solid to constant weight, and obtain 340g of white solid. HPLC: 99.64%. mp = 125–127℃; [α] D 20 =45.6; 1 H-NMR(500MHz,DMSO-d6)δ:7.47(dd,J=8.5,5.5Hz,2H),7.19(t,J=8.9Hz,2H),6.6 6(t,J=8.2Hz,1H), 6.51(dd,J=19.2,8.2,1.1Hz,2H), 5.98(dd,J=13.8,1.2Hz,2H), 5.50 (dd, J = 8.5, 4.6 Hz, 1H), 3.17 (td, J = 11.7, 5.0 Hz, 1H), 3.07 (td, J = 12.1, 11.7, 4.8 Hz, 1H), 2.73 (s, 6H), 2.40–2.27 (m, 1H), 2.25–2.09 (m, 1H). HRMS(ESI) m / z: Calculated value: C 18 H 20 FNO3(M+H) + 318.1500; Measured value: 318.1494.

[0153] Example 2: Preparation of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form I

[0154] 2.1 Static recrystallization method

[0155] 2.1.1 Weigh 0.5 g of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 15 mL of a mixed solution of dichloromethane and n-propanol (volume ratio 2:1), shake thoroughly until the sample is completely dissolved, let stand at room temperature, and a solid will precipitate. Filter, wash, and vacuum dry at 60 °C to obtain crystal form I.

[0156] 2.1.2 Weigh 0.5 g of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 5 mL of a methanol-anhydrous ethanol (volume ratio 1:1) mixture, shake thoroughly until the sample is completely dissolved, let stand at room temperature, and a solid will precipitate. Filter, wash, and vacuum dry at 60 °C to obtain crystal form I.

[0157] 2.1.3 Weigh 0.5 g of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 12 mL of dichloromethane, shake thoroughly until the sample is completely dissolved, let stand at room temperature, and a solid will precipitate. Filter, wash, and vacuum dry at 60 °C to obtain crystal form I.

[0158] 2.1.4 Weigh 0.5 g of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 9 mL of acetone, shake thoroughly until the sample is completely dissolved, let stand at room temperature, and a solid will precipitate out. Filter, wash, and vacuum dry at 60 °C to obtain crystal form I.

[0159] 2.1.5 Weigh 0.5 g of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 6 mL of a mixed solution of N-methylpyrrolidone-isopropanol (volume ratio 1:5), heat at 60 °C until the sample is completely dissolved, let stand at room temperature, and a solid will precipitate. Filter, wash, and vacuum dry at 60 °C to obtain crystal form I.

[0160] 2.1.6 Weigh 0.5 g of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 45 mL of a mixed solution of butanone and methyl tert-butyl ether (volume ratio 1:8), shake thoroughly until the sample is completely dissolved, let stand at room temperature, and a solid will precipitate. Filter, wash, and vacuum dry at 60 °C to obtain crystal form I.

[0161] 2.2 Preparation by solvent removal method

[0162] 2.2.1 Weigh 0.5 g of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 30 mL of a mixed solution of acetonitrile and n-heptane (volume ratio 1:2), heat at 60 °C to aid dissolution, then transfer to a rotary evaporator to remove the solvent. At the end of the experiment, collect the solid, dry it to obtain crystal form I.

[0163] 2.2.2 Weigh 0.5 g of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 20 mL of a methanol-ethyl acetate mixture (volume ratio 1:4), heat at 60 °C to aid dissolution, then transfer to a rotary evaporator to remove the solvent. At the end of the experiment, collect the solid and dry it to obtain crystal form I.

[0164] 2.2.3 Weigh 0.5 g of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 10 mL of 95% ethanol, heat at 60 °C to aid dissolution, and then transfer to a rotary evaporator to remove the solvent. At the end of the experiment, collect the solid to obtain crystal form I.

[0165] 2.2.4 Weigh 0.5 g of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 45 mL of a mixed solution of n-propanol and methyl tert-butyl ether (volume ratio 8:1), shake thoroughly until the sample is completely dissolved, then transfer to a rotary evaporator to remove the solvent. At the end of the experiment, collect the solid to obtain crystal form I.

[0166] 2.2.5 Weigh 0.5 g of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 20 mL of acetonitrile, heat at 60 °C to aid dissolution, and then transfer to a rotary evaporator to remove the solvent. At the end of the experiment, collect the solid to obtain crystal form I.

[0167] 2.2.6 Weigh 0.5 g of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 60 mL of a chloroform-n-hexane (volume ratio 5:1) mixture, shake thoroughly until the sample is completely dissolved, then transfer to a rotary evaporator to remove the solvent. At the end of the experiment, collect the solid to obtain crystal form I.

[0168] 2.3 Preparation using the antisolvent method

[0169] 2.3.1 Weigh about 0.5 g of the sample, add 10 mL of acetonitrile and dissolve it completely at 60 °C. Then quickly pour in about 80 mL of methyl tert-butyl ether, let stand, and a solid will precipitate. Filter, wash, and vacuum dry at 60 °C to obtain crystal form I.

[0170] 2.3.2 Weigh about 0.5 g of the sample, add 5 mL of ethanol and dissolve it completely at 60 °C, then quickly pour in about 30 mL of n-hexane, let it stand, and a solid will precipitate out. Filter, wash, and vacuum dry at 60 °C to obtain crystal form I.

[0171] 2.3.3 Weigh about 0.5 g of the sample, add 2 mL of dimethyl sulfoxide and dissolve it completely at 60 °C. Then quickly pour in about 20 mL of isopropyl ether, let stand, and a solid will precipitate. Filter, wash, and vacuum dry at 60 °C to obtain crystal form I.

[0172] 2.3.4 Weigh about 0.5 g of the sample, add 2 mL of N,N-dimethylformamide and dissolve it completely at 60 °C. Then quickly pour in about 40 mL of ethyl acetate, let stand, and a solid will precipitate. Filter, wash, and vacuum dry at 60 °C to obtain crystal form I.

[0173] 2.3.5 Weigh about 0.5 g of the sample, add 2 mL of methanol and dissolve it completely at 60 °C. Then quickly pour in about 20 mL of methyl tert-butyl ether, let stand, and a solid will precipitate. Filter, wash, and vacuum dry at 60 °C to obtain crystal form I.

[0174] 2.3.6 Weigh about 0.5 g of the sample, add 10 mL of chloroform and shake thoroughly until the sample is completely dissolved. Then quickly pour in about 30 mL of n-hexane, let stand, and a solid will precipitate. Filter, wash, and vacuum dry at 60 °C to obtain crystal form I.

[0175] After testing and analysis, the above-mentioned crystal form I has the following properties: Figure 1 The XRPD diagram shown; as Figure 2 Raman diagram as shown; Figure 3 The DSC diagram shown and as follows Figure 4 The TG graph shown.

[0176] Example 3: Preparation of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form II

[0177] Crystal form II can be prepared, for example, by solvent removal.

[0178] 3.1.1 Weigh 0.5 g of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 25 mL of a mixed solution of acetone and isopropanol (volume ratio 2:3), shake thoroughly until the sample is completely dissolved, then transfer to a rotary evaporator to remove the solvent. At the end of the experiment, collect the solid and dry it to obtain crystal form II.

[0179] 3.1.2 Weigh 0.5 g of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 30 mL of a mixed solution of ethanol and n-butanol (volume ratio 1:2), heat at 60 °C to aid dissolution, then transfer to a rotary evaporator to remove the solvent. After the reaction is complete, collect the solid and dry it to obtain crystal form II.

[0180] After testing and analysis, crystal form II has the following properties: Figure 5 The XRPD diagram shown; as Figure 6 Raman diagram as shown; Figure 7 The DSC diagram shown and as follows Figure 8 The TG graph shown.

[0181] Example 4: Preparation of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate crystal form III

[0182] Crystal form III can be prepared, for example, by an anti-solvent method.

[0183] 4.1.1 Weigh about 0.5 g of (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate, add 5 mL of acetonitrile to dissolve it completely, then quickly pour in about 30 mL of isopropyl ether, let stand, and a solid precipitates out. Filter, wash, and dry under vacuum at 60 °C to obtain crystal form III.

[0184] Analysis revealed that crystal form III possesses the following properties: Figure 9 The XRPD diagram shown; as Figure 10 Raman diagram as shown; Figure 11 The DSC diagram shown and as follows Figure 12 The TG graph shown.

[0185] Test case

[0186] Test Example 1: Solubility Experiment

[0187] 1.1 Experimental Objective

[0188] The solubility of compound (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate in different solvents was investigated.

[0189] 1.2 Experimental Methods

[0190] Experimental conditions: 25℃, humidity 40%. The solubility of the samples was determined. 5-10 mg of each compound represented by Formula I was used, and the solubility of each compound in different solvents was determined.

[0191] 1.3 Experimental Results: The results are shown in Table 5 below:

[0192] Table 5 Solubility of Compound I

[0193]

[0194]

[0195] (1) Easily soluble in: anhydrous methanol, NMP, DMF, DMSO;

[0196] (2) Dissolve in glacial acetic acid;

[0197] (3) Slightly soluble in: purified water, anhydrous ethanol, acetone, dichloromethane, chloroform, acetonitrile, and 95% ethanol;

[0198] (4) Slightly soluble: n-propanol, isopropanol, n-butanol, methyl ethyl ketone;

[0199] (5) Almost insoluble: n-hexane, cyclohexane, n-heptane, methyl tert-butyl ether, petroleum ether, isopropyl ether, ethyl acetate.

[0200] Test Example 2: Mouse Tail Suspension Test

[0201] 2.1 Test Methods

[0202] SPF-grade ICR mice were taken and grouped into groups of 12 mice each according to their weight. The animals were allowed to acclimatize for at least 3 days before behavioral tests were performed.

[0203] Behavioral testing began 1 hour after gavage administration. Mice were placed in a transparent glass cylinder filled with water (15 cm deep, water temperature 23-25℃), and video recorded for 6 minutes (with an LED light panel as the background). At the end of the recording period, the mice were removed from the water, and the next batch of mice was tested. The water was changed after every 3 batches of testing. The videos of the behavioral tests were exported after the experiment and scanned using Forced Swim Scan. TM Software 2.0 was used to analyze the cumulative immobility time of mice during the 4-minute period following a 6-minute forced swimming session.

[0204] The experimental results are expressed as mean ± SD. The t-test was used to compare each group with the solvent group, and P < 0.05 was considered statistically significant.

[0205] 2.2 Test Results

[0206] Duloxetine, 3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate, S-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate, and R-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate (compound I) all showed good dose-response relationships at various dosage groups.

[0207] The minimum effective dose (MED) of duloxetine is 8 mg / kg, and the median effective dose (ED) is... 50 The MED of 3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate is 3.2 mg / kg. 50 The MED of S-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate is 6.4 mg / kg, and the ED is 8.3 mg / kg. 50 The minimum effective dose is 11.4 mg / kg; the minimum effective dose of compound I is 1.6 mg / kg, ED. 50 The result was 7.4 mg / kg. See Table 6 for detailed results.

[0208] Table 6 Results of mouse tail suspension test for each group of compounds

[0209]

[0210] Note: Compared with the solvent group, *P<0.05, **P<0.01.

[0211] Test Example 3: Acute Toxicity Test in Mice

[0212] 3.1 Test Methods

[0213] Based on the doses at which the compound caused 100% and 0% mortality in mice in the preliminary experiment, the dosage and number of groups for the formal experiment were determined. In the formal experiment, ICR mice were randomly divided into groups of 10 mice each (half male and half female), and administered the compound by gavage at a dose of 10 mL / kg. The animals' condition and mortality were observed over 7 days.

[0214] 3.2 Test Results

[0215] In a single-dose toxicity study in mice, the median lethal dose (LD50) of 3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate was... 50 The LD50 of S-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate was 228 mg / kg, with a 95% confidence interval of 195.9–287.7 mg / kg. 50 The LD50 of compound I was 170.5 mg / kg, with a 95% confidence interval of 142.0–208.6 mg / kg. 50 The value was 207 mg / kg, with a 95% confidence interval of 179.0–239.7 mg / kg.

[0216] 3.3 Experimental Conclusions

[0217] The therapeutic index (TI = LD50) was calculated based on the results of acute toxicity and efficacy tests in mice. 50 / ED 50 The results showed that compound I was superior to 3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate and S-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate. Specific data are shown in Table 7.

[0218] Table 7 Results of acute toxicity test in mice

[0219]

[0220] Test Example 4: Experiment on Factors Affecting Crystal Form Stability

[0221] Experimental methods

[0222] High-temperature experiment: Weigh approximately 0.3g of crystal forms I, II, and III respectively, place them in a clean petri dish, and place them at 60℃ for 30 days. Samples were taken on days 0, 5, 10, and 30 for XRPD analysis.

[0223] High humidity experiment: Weigh approximately 0.3g of crystal form I, II, and III samples respectively, place them in clean petri dishes, and place them at a relative humidity of 92.5% for 30 days. Samples were taken on day 0, day 5, day 10, and day 30 for XRPD analysis.

[0224] Illumination experiment: Weigh approximately 0.3g of crystal form I, II, and III samples respectively, place them in a clean petri dish, spread them out, and place them in an illumination chamber (illuminance of 5000 lx) for 30 days. Samples were taken on days 0, 5, 10, and 30 for XRPD analysis.

[0225] Table 8 Experimental Factors Affecting Crystal Form I

[0226] condition 5 days 10 days 30 days high temperature Unchanged Unchanged Unchanged High humidity Unchanged Unchanged Unchanged illumination Unchanged Unchanged Unchanged

[0227] Table 9 Experimental Factors Affecting Crystal Form II

[0228] condition 5 days 10 days 30 days high temperature Unchanged Unchanged Unchanged High humidity Crystal transformation Crystal transformation Crystal transformation illumination Unchanged Unchanged Unchanged

[0229] Table 10 Experimental Factors Affecting Crystal Form III

[0230] condition 5 days 10 days 30 days high temperature Unchanged Unchanged Unchanged High humidity Unchanged Unchanged Unchanged illumination Unchanged Unchanged Unchanged

[0231] Test Example 5: Solubility Experiment

[0232] 5.1 Sample Preparation

[0233] Test solution: Weigh appropriate amounts of different crystal forms of compound I and place them in different test tubes. Add 2 mL of water and place them in a balancing apparatus at 25 °C for 24 hours (supersaturated). Filter and take 1 mL of each filtrate. Place them in different 50 mL volumetric flasks and dilute to the mark with diluent (70% methanol). Shake well to obtain the test solution.

[0234] Reference solution: Accurately weigh an appropriate amount of reference standard, add an appropriate amount of diluent, sonicate to dissolve and dilute to prepare a solution containing approximately 0.15 mg of sample per 1 mL.

[0235] 5.2 Preparation of the mobile phase

[0236] (1) Buffer preparation: Weigh about 2.3460 g of ammonium dihydrogen phosphate, dissolve it in 1000 mL of water, add 2 mL of triethylamine, and adjust the pH to 2.5 with phosphoric acid.

[0237] (2) Preparation of mobile phase

[0238] Mobile phase A: 0.02 mol / L ammonium dihydrogen phosphate solution (2 mL triethylamine was added to every 1000 mL, and the pH was adjusted to 2.5 with phosphoric acid) - acetonitrile (80:20), prepare 1000 mL, mix well, and filter.

[0239] Mobile phase B: 0.02 mol / L ammonium dihydrogen phosphate solution (2 mL triethylamine added per 1000 mL, pH adjusted to 2.5 with phosphoric acid) - acetonitrile (20:80), prepare 1000 mL, mix well, and filter.

[0240] Diluent: 70% methanol

[0241] 5.3 Chromatographic conditions

[0242] Detection wavelength: 215 nm; flow rate: 1.0 mL / min; column temperature: 35 ℃; injection volume: 10 μL; column: Agilent Eclipse Plus C18 column (4.6*250 mm, 5 μm).

[0243] Table 11 Gradient Procedure

[0244] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 3 100 0 20 85 15 30 85 15 40 75 25 55 20 80 60 20 80 61 100 0 70 100 0

[0245] 5.4. Sample Determination

[0246] Accurately transfer 10 μL of each solution into the liquid chromatograph, record the chromatogram, and determine the solubility of the compounds using the external standard method. The results are shown in Table 12.

[0247] Table 12 Solubility of Crystal Forms

[0248]

[0249] Experimental results show that the crystal forms of the compounds shown in Formula I all have good solubility.

[0250] Test Example 6 Hygroscopicity Test

[0251] 6.1 Take a dry, stoppered glass weighing bottle and place it in a suitable 25℃±1℃ constant temperature desiccator (with a saturated solution of ammonium chloride or ammonium sulfate at the bottom) or artificial climate chamber (set temperature 25℃±1℃, relative humidity 80%±2%) one day before the test, and accurately weigh it (m1).

[0252] 6.2 Take an appropriate amount of the crystal form of the test sample I compound, spread it evenly in the weighing bottle mentioned above, and the thickness of the test sample is generally about 1 mm. Accurately weigh the sample (m2).

[0253] 6.3 Leave the weighing bottle open and place it along with the cap under the above-mentioned constant temperature and humidity conditions for 24 hours.

[0254]

[0255] 6.4 Close the weighing bottle cap and accurately weigh the contents (m3). The test results are shown in Table 13.

[0256] Table 13 Hygroscopicity Test

[0257] Drug Name <![CDATA[m1(g)]]> <![CDATA[m2(g)]]> <![CDATA[m3(g)]]> Weight gain (%) Crystal form I 35.21288 35.66194 35.66227 0.07 Crystal form III 33.99131 34.49240 34.49262 0.04

[0258] Experimental conclusion: Different crystal forms of the compound of formula I all show no or almost no hygroscopicity, therefore no strict packaging requirements are required during storage.

[0259] Test Example 7: Pharmacokinetic Experiment

[0260] Table 14 Dosing Regimen

[0261]

[0262] Each group consists of 2 Beagles, half male and half female, purchased from Jiangsu Lingfu Zhaoshengyuan Biotechnology Co., Ltd.

[0263] Solution preparation:

[0264] 1) Intravenous administration: 0.9% physiological saline as solvent;

[0265] 2) Oral administration: The drug was weighed according to the actual weight of the animal at a dose of 5 mg / kg, and then filled into capsules and administered to the animal. The test results are shown in Table 15.

[0266] Table 15 Results of pharmacokinetic studies without crystal form

[0267] Group Crystal form I Crystal form I Crystal form III route of administration vein oral oral Dosage (mg / kg) 0.5 5 5 Pharmacokinetic parameters mean mean mean <![CDATA[t 1 / 2 (h)]]> 2.67 3.48 3.86 <![CDATA[T max (h)]]> 0.29 0.63 0.75 <![CDATA[C max (ng / mL)]]> 70.96 49.75 19.75 <![CDATA[AUC (0-t) (μg / L*h)]]> 148.21 198.64 103.58 <![CDATA[AUC (0-∞) (μg / L*h)]]> 156.52 200.65 105.28 Bioavailability (%) / 12.82 6.73

[0268] Experimental conclusions: Pharmacokinetic experiments showed that the crystal form of compound I has good bioavailability, especially crystal form I.

[0269] The above description is merely a preferred embodiment of this application and is not intended to limit the scope of this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A (R)-3-[(benzo[d][1,3]dioxolane-4-yl)oxy]- N,N- Crystal form I of dimethyl-3-(4-fluorophenyl)propylamine oxalate, characterized in that, The X-ray powder diffraction pattern of crystal form I includes diffraction peaks located at 2θ of 9.33±0.2°, 15.64±0.2°, 20.06±0.2°, 23.63±0.2°, and 24.21±0.2°. 。 2. The crystal form I according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form I also includes diffraction peaks located at 2θ of 16.48±0.2°, 19.77±0.2°, 22.09±0.2° and 23.06±0.2°.

3. The crystal form I according to claim 2, characterized in that, The melting endothermic peak of the DSC diagram of crystal form I is selected from 126.8 ℃ to 132.2 ℃.

4. The crystal form I according to claim 3, characterized in that, The melting endothermic peak of the DSC diagram for crystal form I is 129.8 °C.

5. The crystal form I according to claim 3, characterized in that, The X-ray powder diffraction pattern of crystal form I is basically shown in Figure 1; or The DSC spectrum of crystal form I is basically shown in Figure 3.

6. A pharmaceutical composition comprising crystal form I according to any one of claims 1-5, and one or more pharmaceutically acceptable carriers, diluents or excipients.

7. Use of a crystal form I according to any one of claims 1-5, or the pharmaceutical composition according to claim 6, in the preparation of a medicament, wherein the medicament is used for the prevention and / or treatment of mental illnesses.

8. The use according to claim 7, wherein the mental illness is selected from one or more of anxiety disorder, obsessive-compulsive disorder, depression, phobia and schizophrenia.

9. The use according to claim 7, wherein the mental illness is depression.

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